Study of Durvalumab+Olaparib or Durvalumab After Treatment With Durvalumab and Chemotherapy in Patients With Lung Cancer (ORION)

NCT ID: NCT03775486

Last Updated: 2025-10-21

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 401 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-12-21
• Study Completion Date: 2026-09-27

Brief Summary

This is a randomized, double-blind, multi-center, global Phase II study to determine the efficacy and safety of Durvalumab plus Olaparib combination therapy compared with Durvalumab monotherapy as maintenance therapy in patients whose disease has not progressed following Standard of Care (SoC) platinum-based chemotherapy with Durvalumab as first-line treatment in patients with Stage IV non small-cell lung cancer (NSCLC) with tumors that lack activating epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) fusions.

Detailed Description

Adult patients with a histologically or cytologically documented advanced NSCLC not amenable to curative surgery or radiation with tumors that lack activation EGFR mutations and ALK fusions are eligible for enrollment. During the initial therapy phase, patients will receive treatment with Durvalumab along with the Investigator's choice of platinum-based doublet therapy for squamous NSCLC (nab-paclitaxel plus carboplatin or gemcitabine plus carboplatin/cisplatin) and non-squamous NSCLC (nab-paclitaxel plus carboplatin or pemetrexed plus carboplatin/cisplatin) for 4 cycles. Patients who have completed 4 cycles and not progressed throughout the initial therapy phase will be randomized in a 1:1 ratio into the maintenance phase of the study to receive either Durvalumab plus placebo or Durvalumab plus Olaparib maintenance therapy. Patients will receive maintenance treatment until specific discontinuation criteria are met, including clinical disease progression (as assessed by the Investigator) or RECIST 1.1-defined radiological Progressive Disease (PD), unacceptable toxicity, and withdrawal of consent. Tumor evaluation scans will be performed until objective disease progression as efficacy assessments. All patients will be followed for survival until the end of the study.

Conditions

Non-small Cell Lung Cancer NSCLC

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Durvalumab/Olaparib Combination Therapy

Durvalumab/Olaparib Combination Therapy:

Durvalumab/SoC chemotherapy (initial therapy phase) followed by Durvalumab/Olaparib (maintenance phase)

Group Type: EXPERIMENTAL

Durvalumab

Intervention Type: DRUG

Initial therapy phase: IV infusion q3w for 4 cycles. Maintenance phase: IV infusion q4w.

Olaparib

Intervention Type: DRUG

150-mg tablets (2 × 150-mg tablets for 300-mg dose) 100-mg tablet available if dose reductions are required

Nab-paclitaxel+carboplatin

Intervention Type: DRUG

Standard of Care chemotherapy (squamous and non-squamous patients)

Gemcitabine+carboplatin

Intervention Type: DRUG

Standard of Care chemotherapy (squamous patients only)

Pemetrexed+carboplatin

Intervention Type: DRUG

Standard of Care chemotherapy (non-squamous patients only)

Gemcitabine+cisplatin

Intervention Type: DRUG

Standard of Care chemotherapy (squamous patients only)

Pemetrexed+cisplatin

Intervention Type: DRUG

Standard of Care chemotherapy (non-squamous patients only)

Durvalumab Monotherapy

Durvalumab Monotherapy: Durvalumab/SoC chemotherapy (initial therapy phase) followed by Durvalumab/placebo (maintenance phase)

Group Type: EXPERIMENTAL

Durvalumab

Intervention Type: DRUG

Initial therapy phase: IV infusion q3w for 4 cycles. Maintenance phase: IV infusion q4w.

Placebo for Olaparib

Intervention Type: DRUG

Matching tablet

Nab-paclitaxel+carboplatin

Intervention Type: DRUG

Standard of Care chemotherapy (squamous and non-squamous patients)

Gemcitabine+carboplatin

Intervention Type: DRUG

Standard of Care chemotherapy (squamous patients only)

Pemetrexed+carboplatin

Intervention Type: DRUG

Standard of Care chemotherapy (non-squamous patients only)

Gemcitabine+cisplatin

Intervention Type: DRUG

Standard of Care chemotherapy (squamous patients only)

Pemetrexed+cisplatin

Intervention Type: DRUG

Standard of Care chemotherapy (non-squamous patients only)

Interventions

Durvalumab

Initial therapy phase: IV infusion q3w for 4 cycles. Maintenance phase: IV infusion q4w.

Intervention Type: DRUG

Placebo for Olaparib

Matching tablet

Intervention Type: DRUG

Olaparib

150-mg tablets (2 × 150-mg tablets for 300-mg dose) 100-mg tablet available if dose reductions are required

Intervention Type: DRUG

Nab-paclitaxel+carboplatin

Standard of Care chemotherapy (squamous and non-squamous patients)

Intervention Type: DRUG

Gemcitabine+carboplatin

Standard of Care chemotherapy (squamous patients only)

Intervention Type: DRUG

Pemetrexed+carboplatin

Standard of Care chemotherapy (non-squamous patients only)

Intervention Type: DRUG

Gemcitabine+cisplatin

Standard of Care chemotherapy (squamous patients only)

Intervention Type: DRUG

Pemetrexed+cisplatin

Standard of Care chemotherapy (non-squamous patients only)

Intervention Type: DRUG

Other Intervention Names

MEDI4736 (Durvalumab); Placebo; AZD2281 (Olaparib)

Eligibility Criteria

Inclusion Criteria

• Histologically or cytologically documented Stage IV NSCLC not amenable to curative surgery or radiation.

Patients must have tumors that lack activating EGFR mutations and ALK fusions.

• (WHO)/(ECOG) performance status of 0 or 1
• No prior chemotherapy or any other systemic therapy for Stage IV NSCLC
• Adequate organ and marrow function without blood transfusions in the past 28 days,
• At least 1 tumor lesion, not previously irradiated, that can be accurately measured as per RECIST 1.1.

• Documented radiographic evidence of CR, PR, or Stable Disease (SD) as per Investigator-assessed RECIST 1.1 following 4 cycles of platinum-based chemotherapy.
• Creatinine Clearance (CrCl) ≥51 mL/min calculated by the investigator or designee using the Cockcroft-Gault equation or measured by 24-hour urine collection.
• Ability to swallow whole oral medications.
• All patients must provide a formalin-fixed, paraffin embedded tumor sample for tissue-based immunohistochemistry staining and DNA sequencing to determine PD-L1 expression, HRRm status, and other correlatives: either newly acquired or archival tumor samples (<3 years old) are acceptable. If available, a newly acquired tumor biopsy, collected as part of routine clinical practice, is preferred. If not available, an archival sample taken <3 years prior to screening is acceptable. If both an archival sample and a fresh tumor biopsy sample are available, both samples should be submitted for analysis and must be submitted as different samples using different accession numbers. Slides from different blocks cannot be mixed and submitted with the same kit.

Exclusion Criteria

• Mixed small-cell lung cancer and sarcomatoid variant NSCLC histology.
• Prior exposure to any chemotherapy agents (except chemotherapy or chemoradiation for non-metastatic disease), polyadenosine 5'diphosphoribose [poly (ADP ribose)] polymerase (PARP) therapy, or immunomediated therapy
• Active or prior documented autoimmune or inflammatory disorders.
• Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of Investigational Product (IP)
• untreated (CNS) metastases and/or carcinomatous meningitis
• Active infection.

• Inability to complete 4 cycles of platinum-based chemotherapy for any reason or discontinuation of Durvalumab during initial therapy.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 130 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Myung-Ju Ahn, MD

Role: PRINCIPAL_INVESTIGATOR

Sungkyunkwan University School of Medicine, 135-710, Seoul, Korea

Locations

Research Site

Bonita Springs, Florida, United States

Research Site

St. Petersburg, Florida, United States

Research Site

Tallahassee, Florida, United States

Research Site

West Palm Beach, Florida, United States

Research Site

Kansas City, Missouri, United States

Research Site

Bethlehem, Pennsylvania, United States

Research Site

Chattanooga, Tennessee, United States

Research Site

Nashville, Tennessee, United States

Research Site

Houston, Texas, United States

Research Site

Aalst, , Belgium

Research Site

Leuven, , Belgium

Research Site

Roeselare, , Belgium

Research Site

Budapest, , Hungary

Research Site

Budapest, , Hungary

Research Site

Debrecen, , Hungary

Research Site

Deszk, , Hungary

Research Site

Farkasgyepü, , Hungary

Research Site

Törökbálint, , Hungary

Research Site

Ahmedabad, , India

Research Site

Ahmedabad, , India

Research Site

Jamnagar, , India

Research Site

Kochi, , India

Research Site

Mysuru, , India

Research Site

Nashik, , India

Research Site

Nashik, , India

Research Site

Nashik, , India

Research Site

Pune, , India

Research Site

Thiruvananthapuram, , India

Research Site

Chūōku, , Japan

Research Site

Kanazawa, , Japan

Research Site

Kurume-shi,, , Japan

Research Site

Matsuyama, , Japan

Research Site

Nagoya, , Japan

Research Site

Sendai, , Japan

Research Site

Sunto-gun, , Japan

Research Site

Ube-shi, , Japan

Research Site

Chihuahua City, , Mexico

Research Site

Culiacán, , Mexico

Research Site

San Luis Potosí City, , Mexico

Research Site

Blaricum, , Netherlands

Research Site

Harderwijk, , Netherlands

Research Site

Tilburg, , Netherlands

Research Site

Bialystok, , Poland

Research Site

Lodz, , Poland

Research Site

Poznan, , Poland

Research Site

Prabuty, , Poland

Research Site

Arkhangelsk, , Russia

Research Site

Chelyabinsk, , Russia

Research Site

Kursk, , Russia

Research Site

Moscow, , Russia

Research Site

Nal'chik, , Russia

Research Site

P. Herzen Moscow Oncology Rese, , Russia

Research Site

Saint Petersburg, , Russia

Research Site

Sochi, , Russia

Research Site

Yaroslavl, , Russia

Research Site

Dongjakgu, , South Korea

Research Site

Goyang-si, , South Korea

Research Site

Seodaemun-gu, , South Korea

Research Site

Seoul, , South Korea

Research Site

Seoul, , South Korea

Research Site

Suweonsi Paldalgu, , South Korea

Research Site

Dnipro, , Ukraine

Research Site

Kharkiv Region, , Ukraine

Research Site

Kirovohrad, , Ukraine

Research Site

Odesa, , Ukraine

Research Site

Uzhhorod, , Ukraine

Research Site

Zaporizhzhia, , Ukraine

Research Site

Dundee, , United Kingdom

Research Site

Hull, , United Kingdom

Countries

United States; Belgium; Hungary; India; Japan; Mexico; Netherlands; Poland; Russia; South Korea; Ukraine; United Kingdom

References

Ahn MJ, Bondarenko I, Kalinka E, Cho BC, Sugawara S, Galffy G, Shim BY, Kislov N, Nagarkar R, Demedts I, Gans SJM, Mendoza Oliva D, Stewart R, Lai Z, Mann H, Shi X, Hussein M. Durvalumab in Combination With Olaparib Versus Durvalumab Alone as Maintenance Therapy in Metastatic NSCLC: The Phase 2 ORION Study. J Thorac Oncol. 2023 Nov;18(11):1594-1606. doi: 10.1016/j.jtho.2023.06.013. Epub 2023 Jun 29.

Reference Type: DERIVED

PMID: 37390980 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

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Other Identifiers

2018-003460-30

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

D9102C00001

Identifier Type: -

Identifier Source: org_study_id